Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity
Loss of Hsp90 association up-regulates Src-dependent ErbB2 activity
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DOI：
10.1128/mcb.00899-06
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发表时间：
2007-01-01
影响因子：
5.3
通讯作者：
Neckers, Len
中科院分区：
文献类型：
--
作者：
Xu, Wanping;Yuan, Xitong;Neckers, Len
受体酪氨酸激酶ErbB2在肿瘤发生中起重要作用。我们以前已经证明，分子伴侣Hsp90通过与激酶域N叶的短环结构结合来保护ErbB2免受蛋白酶体介导的降解。在这里，我们发现Hsp90结合的丧失与ErbB2激酶活性的增强及其反式激活潜力有关，同时伴随着位于激活域的激活环中的Tyr877的结构性增强的磷酸化。我们进一步证明，Tyr877的磷酸化是由Src介导的，这是ErbB2蛋白活性增强所必需的。最后，对激活域的计算机模拟表明激活环依赖于磷酸化的重定向，这表明Tyr877磷酸化对ErbB2活性的重要性。这些发现表明，Hsp90与ErbB2结合参与了对激酶活性和稳定性的调节。
The receptor tyrosine kinase ErbB2 plays a crucial role in tumorigenesis. We showed previously that the molecular chaperone Hsp90 protects ErbB2 from proteasome-mediated degradation by binding to a short loop structure in the N-lobe of the kinase domain. Here we show that loss of Hsp90 binding correlates with enhanced ErbB2 kinase activity and its transactivating potential, concomitant with constitutively increased phosphorylation of Tyr877, located in the activation loop of the kinase domain. We show further that Tyr877 phosphorylation is mediated by Src and that it is necessary for the enhanced kinase activity of ErbB2. Finally, computer modeling of the kinase domain suggests a phosphorylation-dependent reorientation of the activation loop, denoting the importance of Tyr877 phosphorylation for ErbB2 activity. These findings suggest that Hsp90 binding to ErbB2 participates in regulation of kinase activity as well as kinase stability.